N(Sulfonyl)anilines for treating angina pectoris

ABSTRACT

The invention relates to novel aniline derivatives of the formula: ##STR1## wherein R 1  and R 2  represent a hydrogen or chlorine atom, an allyloxy, acetamide or carboxamide group, R 3  represents a methyl or an optionally substituted phenyl group, R 4  represents a hydrogen atom and R 5  an isopropyl, terbutyl, 2-phenoxy-ethyl or 3-phenyl-propyl group or R 3  and R 5  taken together form with the nitrogen atom a substituted heterocyclic group. 
     The compounds of the invention are useful for the treatment of angina pectoris.

This invention relates to novel aniline derivatives and to pharmaceutical compositions containing the same. The invention also relates to a process for preparing these aniline derivatives and to a method of treatment of angina pectoris.

The aniline derivatives with which the invention is concerned are the compounds of the general formula: ##STR2## and the pharmaceutically acceptable acid addition salts thereof, wherein R₁ and R₂, which are the same or different, represent an allyloxy, acetamide or carboxamide group, or a hydrogen or chlorine atom, R₃ represents a methyl, phenyl, methylphenyl or methoxyphenyl group, R₄ represents a hydrogen atom and R₅ an isopropyl, terbutyl, 2-phenoxyethyl, 3-phenylpropyl group or R₄ and R₅ taken together form with the nitrogen atom a heterocycle such as pyrrole, morpholine, a substituted piperazine of the formula: ##STR3## wherein R₆ represents a straight-chain alkyl group containing from 1 to 3 carbon atoms, a 2-hydroxyethyl, a benzyl or a 2-pyridyl group or a phenyl group optionally substituted by either a halogen atom or by a methoxy radical.

The compounds of formula I can be prepared by reacting an amine of the general formula: ##STR4## wherein R₄ and R₅ have the same meanings as hereabove, with a compound of the general formula: ##STR5## wherein R₁, R₂ and R₃ have the same meanings as hereabove. This reaction is carried out in an alcoholic solvent such as, for example, ethanol.

The amines of formula III are compounds which are readily available on the market.

The epoxides of formula IV are prepared by condensing a sulphonamide of the general formula: ##STR6## wherein R₁, R₂ and R₃ have the same meanings as hereabove, with an epihalohydrine such as, for example, epichlorhydrine.

The sulphonamides of formula V are prepared by condensing a substituted aniline of the formula: ##STR7## wherein R₁ and R₂ have the same meanings as hereabove, with a sulphonyl chloride of the formula:

    Cl--SO.sub.2 R.sub.3                                       VII

wherein R₃ has the same meanings as hereabove.

The anilines of formula VI are either commercially available or have been described by G. D. Tiffany in J. Am. Chem. Soc., 1948, 70, 592 and by J. Degutis and D. Sukeliene in Zh. Obshch. Khim. 1961, 31, 3326. The sulphonyl chlorides of formula VII are available on the market. The compounds of the invention have been found to possess useful pharmacological properties likely to render them of particular value in the treatment of pathological conditions of the heart.

More particularly, they have been found to possess very useful properties for the treatment of angina pectoris.

Another object of the invention is therefore a method of treatment of pathological conditions of the heart, in particular angina pectoris, consisting in administering to a patient in need of such treatment at least one compound of formula I or one of its non-toxic acid addition salts.

It is well known that pathological conditions of the heart are very difficult diseases to master.

This is particularly true in the case of angina pectoris, since there are many factors which may provoke an attack of angor.

The considerable number of factors thus involved justifies the presentday approach to the therapeutic treatment of angina pectoris. According to modern thinking, the medicinal value of an active principle is in direct proportion to the polyvalent nature of its pharmacological activity.

It has been found that the compounds of the invention provoke bradycardia and diminish arterial pressure, properties which are useful for obtaining a better energetic performance of the myocardium. It has also been found that the compounds of the invention possess valuable antiadrenergic properties, not only with respect to the α system but also to the β system.

These properties enable the heart to be protected against the hypermetabolic action of the catecholamines and, as a result also contribute to improving cardiac performance.

The pharmacological investigation was carried out on anaesthetized dogs (30 mg/kg I.V. of sodium pentobarbital) having previously received an intravenous dose of 1 mg/kg of atropine sulphate.

The substance to be tested was given by an intravenous injection lasting two minutes after which the behaviour of both heart-rate and blood-pressure was observed over a certain period of time. An investigation was then carried out to detect any antiadrenergic properties. The compound listed hereunder were tested, in most cases in the form of pharmaceutically acceptable acid addition salts:

    ______________________________________                                                                       N°                                        Compounds                     code                                             ______________________________________                                         2-Allyloxy-N-(3-tert-butylamino-2 hydroxy-                                     propyl)-N-(4-methoxy-benzenesulphonyl)-aniline                                                               14                                               2-Allyloxy-N-[3-(4-(4-fluoro-phenyl)-1-piperazi-                               nyl)-2-hydroxy-propyl]-N-methylsulphonyl-aniline                                                             23                                               2-Allyloxy-N-[2-hydroxy-3-(4-(2-methoxy-phenyl)-                               1-piperazinyl)-propyl]-N-methylsulphonyl-aniline                                                             30                                               2-Allyloxy-N-[3-(4-benzyl-1-piperazinyl)-2-hydroxy-                            propyl]-N-(4-methylbenzene-sulphonyl)-aniline                                                                40                                               2-Allyloxy-N-[2-hydroxy-3-(4-(2-pyridyl)-1-pipera-                             zinyl)-propyl]-N-(4-methoxy-benzenesulphonyl)-aniline                                                        53                                               2-Allyloxy-N-[2-hydroxy-3-(4-(2-fluoro-phenyl)-1-                              piperazinyl)-propyl]-N-(4-methoxy-benzenesulphonyl)-                           aniline                       57                                               3,4-Dichloro-N-[3-(4-(2-chloro-phenyl)-1-piperazinyl)-                         2-hydroxy-propyl]-N-methylsulphonyl-aniline                                                                  75                                               3,4-Dichloro-N-[2-hydroxy-3-(4-(2-methoxy-phenyl)-                             1-piperazinyl)-propyl]-N-methylsulphonyl-aniline                                                             77                                               3,4-Dichloro-N-[3-(4-(4-chloro-phenyl)-1-piperazi-                             nyl)-2-hydroxy-propyl]-N-(4-methoxy-benzenesulphonyl)-                         aniline                       84                                               4-Acetylamino-N-[2-hydroxy-3-(4-phenyl-1-piperazinyl)-                         propyl]-N-methylsulphonyl-aniline                                                                            88                                               4-Acetylamino-N-[2-hydroxy-3-(4-(2-methoxy-phenyl)1-                           piperazinyl)-2-hydroxy-propyl]-N-methyl-sulphonyl-                             aniline                       90                                               4-Acetylamino-N-[2-hydroxy-3-(4-phenyl-1-piperazinyl)-                         propyl]-N-(4-methyl-benzenesulphonyl)-aniline                                                                91                                               4-Acetylamino-N-[2-hydroxy-3-(4-(2-methoxy-phenyl)-                            1-piperazinyl)-propyl]-N-(4-methyl-benzenesulphonyl)-                          aniline                       94                                               4-Acetylamino-N-[3-(4-(2-chloro-phenyl)-1-piperazi-                            nyl)-2-hydroxy-propyl]-N-(4-methyl-benzenesulphonyl)-                          aniline                       95                                               N-[3-(4-(4-chlorophenyl)-1-piperazinyl)-2-hydroxy-                             propyl]-N-methylsulphonyl-4-amino-phenylacetamide                                                            99                                               N-[2-hydroxy-3-(4-(2-methoxy-phenyl)-1-piperazinyl)-                           propyl]-N-methylsulphonyl-4-amino-phenylacetamide                                                            102                                              N-[2-hydroxy-3-(4-(2-methoxy-phenyl)-1-piperazino)-                            propyl]-N-(4-methyl-benzenesulphonyl)-4-amino-                                 phenylacetamide               105                                              ______________________________________                                    

The following observations were made:

(1) Heart-rate

At a dose of 10 mg/kg, Compounds Nos. 14, 40, 57, 77, 84, 91, 94 and 102 provoked a marked and long-lasting reduction in heart-rate.

(2) Blood-pressure

At a dose of 10 mg/kg, Compounds Nos. 23, 30, 40, 53, 75, 77, 88, 90, 91, 94, 95, 102 and 105 caused a marked and constant reduction in blood-pressure.

(3) Antiadrenergic properties

The inhibitory effect of the compounds of the invention on the α-system was first determined by measuring the degree to which the said compounds reduced epinephrine-increased blood-pressure in the atropinized dog.

A dose of epinephrine, sufficient to produce a stable increase in blood-pressure was administered to a dog anaesthetized with sodium pentobarbital which had previously received an intravenous injection of 1 mg/kg of atropine sulphate. The operation was repeated several times and the blood-pressure obtained was noted. When the latter had returned to its normal level, the animal was given an intravenous dose of 10 mg/kg of the compound to be tested followed by the same dose as above of epinephrine.

Blood-pressure was recorded throughout the trial and it was observed that Compounds Nos. 14, 23, 30, 40, 53, 57, 75, 77, 84, 88, 90, 91, 94, 99, 102 and 105 reduced, at least partially, the epinephrine-induced arterial hypertension.

Long-lasting and total reduction was obtained with a dose as low as 2 mg/kg, for instance with Compounds Nos. 30 and 102.

The antiadrenergic effects of the compounds of the invention on the β-system were also studied, by determining the degree to which they reduced isoprenaline-increased heart-rate. The same method as above was used.

Compounds Nos. 14, 30, 40 and 88 produced a marked reduction in the isoprenaline-increased heart-rate, thus showing considerable β-antiadrenergic properties.

It is well known that the efficacy of an antianginal drug is at its maximum when the α antiadrenergic action is coupled with a β-antiadrenergic action and when the drug also causes a reduction in blood-pressure and heart-rate.

The compounds cited hereabove possess these properties and are therefore the preferred compounds of the invention.

Acute toxicity tests were also carried out on the rat, by intravenous route.

The LD₅₀ of Compound No. 40, i.e. the dose which kills half of the animals treated, was found to be 12 mg/kg.

For therapeutic use in the treatment of angor, 100 to 200 mg of the compounds of the invention will be administered daily in the form of a pharmaceutical composition containing an active principle at least one compound of formula I, or a pharmaceutically acceptable addition salt thereof together with a suitable excipient or carrier therefor.

The compounds of the invention will normally be adminstered in the form of a pharmaceutical composition appropriate to the desired mode of administration. Thus, the pharmaceutical composition may take the form of, for example, a coated or uncoated tablet or of a hard- or soft-gelatine capsule for oral administration or of a solution for injection or of a suppository for rectal administration.

Irrespective of the form which the pharmaceutical composition takes, the latter will normally comprise at least one of the compounds of formula I or a pharmaceutically acceptable acid addition salt thereof in association with an appropriate pharmaceutical excipient or carrier comprising, for example, one or more of the following substances: milk, sugar, starches, talc, magnesium stearate, polyvinylpyrrolidone, alginic acid, colloidal silica or a flavouring agent.

The following Example illustrates, in a non-limitative manner, the process for preparing the compounds of the invention.

PREPARATION OF 2-ALLYLOXY-N-(2-HYDROXY-3-ISOPROPYLAMINO-PROPYL)-N-METHYLSULPHONYL-ANILINE (a) 2-Allyloxy-N-methylsulphonyl aniline

In a two-liter three-necked flask, fitted with a mechanical stirrer, a dropping-funnel and an air-inlet, were dissolved 149.2 g (1 mol) of 2-allyloxy-aniline in a mixture of 500 ml of benzene and 190 ml of pyridine.

A solution of 114.5 g (1 mol) of methane-sulphonylchloride in 195 ml of dimethylformamide and 70 ml of benzene was added drop-by-drop at room temperature.

The reaction medium was stirred at room-temperature for 24 hours and was poured into water.

Stirring was continued for one hour and the insoluble matter was filtered out.

The organic phase was decanted and the excess of pyridine was eliminated by washing with 20% hydrochloric acid.

The organic phase was then washed twice with water and then dried on anhydrous calcium sulphate.

The solvent was evaporated off under reduced pressure and the residue was recrystallized from isopropanol to give 178 g of 2-allyloxy-N-methylsulphonyl-aniline.

Yield: 78.3%. Melting Point: 90° C.

By following the same procedure as that described above but using the appropriate starting-products, the following compounds were prepared:

    ______________________________________                                                                  Melting                                               Compounds                Point °C.                                      ______________________________________                                         2-Allyloxy-N-(4-methyl-benzenesulphonyl)-                                                               102                                                   aniline                  (isopropanol)                                         2-Allyloxy-N-(4-methoxy-benzenesulphonyl)-                                                               98                                                   aniline                  (isopropanol)                                         2,6-Dichloro-N-benzenesulphonyl-aniline                                                                 156                                                                            (ether)                                               2,6-Dichloro-N-(4-methyl-benzenesulphonyl)-                                                             158                                                   aniline                  (isopropanol)                                         3,4-Dichloro-N-methylsulphonyl-aniline                                                                  174                                                                            (ethanol)                                             3,4-Dichloro-N-(4-methyl-benzenesulphonyl)-                                                             150                                                   aniline                  (isopropanol)                                         4-Acetylamino-N-(4-methyl-benzenesulphonyl)-                                                            184                                                   aniline                  (petroleum                                                                     ether                                                                          40/80)                                                3,4-Dichloro-N-(4-methoxy-benzenesulphonyl)-                                                             90                                                   aniline                  (isopropanol)                                         4-Acetylamino-N-methylsulphonyl-aniline                                                                 208                                                                            (methanol)                                            N-Methylsulphonyl-4-amino-phenylacetamide                                                               206                                                                            (methanol)                                            N-(4-methyl-benzenesulphonyl)-4-amino-                                                                  162                                                   phenylacetamide          (isopropanol)                                         ______________________________________                                    

(b) 2-Allyloxy-N-[(2,3-epoxy)-propyl]-N-methylsulphonyl-aniline

In a 500 ml three-necked flask, fitted with a mechanical stirrer, a dropping-funnel and a calcium chloride trap, was introduced a suspension of 5.1 g of sodium hydride in 120 ml of dimethylformamide.

While the reaction medium was maintained at or below room temperature, a solution of 55 g. (0.24 mol) of 2-allyloxy-N-methylsulphonyl-aniline was added drop-by-drop and 40 ml of epichlorhydrine were added in one operation. Stirring was continued for three days at room temperature and the reaction medium was poured into water and extracted three times with ether. The organic phase was washed with water and dried on anhydrous calcium sulphate.

The ether was evaporated off and the solid residue was recrystallized from methanol to give 36.5 g of 2-allyloxy-N-[(2,3-epoxy)-propyl]-N-methylsulphonyl-aniline.

Yield: 66.4%. Melting Point: 78° C.

By following the same procedure but using the appropriate starting-products, the compounds listed hereunder were prepared:

    ______________________________________                                                                   Melting                                              Compounds                 Point °C.                                     ______________________________________                                         2-Allyloxy-N-[(2,3-epoxy)-propyl]-N-                                                                     not analysed                                         (4-methyl-benzenesulphonyl)-aniline                                            2-Allyloxy-N-[(2,3-epoxy)-propyl]-N-                                                                     not analysed                                         (4-methoxy-benzenesulphonyl)-aniline                                           2,6-Dichloro-N-[(2,3-epoxy)-propyl]-N-                                                                   126-127                                              benzenesulphonyl-aniline  (isopropanol)                                        2,6-Dichloro-N-[(2,3-epoxy)-propyl]-N-                                                                   126                                                  (4-methyl-benzenesulphonyl)-aniline                                                                      (isopropanol)                                        3,4-Dichloro-N-[(2,3-epoxy)-propyl]-N-                                                                    75                                                  methylsulphonyl-aniline   (isopropanol/                                                                  chloroforme)                                         3,4-Dichloro-N-[(2,3-epoxy)-propyl]-N-                                                                   200                                                  (4-methyl-benzenesulphonyl)-aniline                                                                      (isopropanol/                                                                  chloroforme)                                         3,4-Dichloro-N-[(2,3-epoxy)-propyl]-N-                                                                   110                                                  (4-methoxy-benzenesulphonyl)-aniline                                                                     (isopropanol)                                        4-Acetylamino-N-[(2,3-epoxy)-propyl]-                                                                    136-140                                              N-methylsulphonyl-aniline (isopropanol)                                        4-Acetylamino-N-[(2,3-epoxy)-propyl]-N-                                                                  114-115                                              (4-methyl-benzenesulphonyl)-aniline                                                                      (isopropanol)                                        N-[(2,3-epoxy)-propyl]-N-methylsulphonyl-                                                                154-159                                              4-amino-phenylacetamide   (methanol)                                           N-[(2,3-epoxy)-propyl]-N-(4-methyl-benzene-                                                              137-140                                              sulphonyl)-4-amino-phenylacetamide                                                                       (isopropanol)                                        ______________________________________                                    

(c) 2-Allyloxy-N-(2-hydroxy-3-isopropylamino-propyl)-N-methylsulphonylaniline--Hydrochloride

In a one-liter flask were dissolved 56.7 g (0.2 mol) of 2-allyloxy-N-[(2,3-epoxy)-propyl]-N-methylsulphonyl-aniline and 50 ml of isopropylamine in 300 ml of absolute ethanol. The reaction medium was refluxed for 24 hours and the excess of isopropylamine and the solvent was eliminated by evaporation under reduced pressure.

The residue was dissolved in ether and a saturated solution of hydrochloric acid in ether was added.

The hydrochloride precipitated and was filtered and recrystallized from isopropanol to give 58.5 g of 2-allyloxy-N-(2-hydroxy-3-isopropylaminopropyl)-N-methylsulphonyl-aniline.

Yield: 77.4%. Melting Point: 139°-141° C.

By following the same procedure but using the appropriate starting products, the compounds listed hereunder were prepared:

    ______________________________________                                                                    Melting                                             Compounds                  Point °C.                                    ______________________________________                                         2-Allyloxy-N-(3-terbutylamino-2-hydroxy-                                       propyl)-N-methylsulphonyl-aniline.                                                                        183                                                 Hydrochloride              (isopro-                                                                       panol)                                              2-Allyloxy-N-methylsulphonyl-N-[(2-phenoxy-                                    ethyl)-3-amino-2-hydroxy-propyl]-aniline.                                                                 118-120                                             p-toluenesulphonate.       (isopro-                                                                       panol)                                              2-Allyloxy-N-methylsulphonyl-N-(2-hydroxy-3-                                                              119-121                                             pyrrolidino-propyl)-aniline. Acid oxalate                                                                 (ethyl                                                                         acetate/                                                                       methanol)                                           2-Allyloxy-N-methysulphonyl-N-[2-hydroxy-                                      (3-phenyl-propyl)-3-amino-propyl]-aniline.                                                                154-156                                             Acid oxalate               (ethyl                                                                         acetate/                                                                       methanol)                                           2-Allyloxy-N-methylsulphonyl-N-(2-hydroxy-                                                                146-151                                             3-morpholino-propyl)-aniline. Acid oxalate                                                                (isopro-                                                                       panol)                                              2-Allyloxy-N-methylsulphonyl-N-[2-hydroxy-3-(4-                                methyl-piperazinyl)-propyl]-aniline.                                                                      223-229                                             Dihydrochloride            (isopro-                                                                       panol)                                              2-Allyloxy-N-methylsulphonyl-N-[3-(4-ethyl-                                    1-piperazinyl)-2-hydroxy-propyl]-aniline.                                                                 211-213                                             Dihydrochloride            (acetone)                                           2-Allyloxy-N-methylsulphonyl-N-[2-hydroxy-3-                                   (4-propyl-1-piperazinyl)-propyl]-aniline.                                                                 186-189                                             Dihydrochloride            (acetone)                                           2-Allyloxy-N-methylsulphonyl-N-[2-hydroxy-                                     3-(4-phenyl-1-piperazinyl)-propyl]-aniline.                                                               127-131                                             Dihydrochloride            (acetone)                                           2-Allyloxy-N-[3-(4-(4-fluoro-phenyl)-1-pipera-                                 zinyl)-2-hydroxy-propyl]-N-methylsulphonyl-                                                               174-180                                             aniline. Acid oxalate      (acetone)                                           2-Allyloxy-N-[3-(4-(2-hydroxy-ethyl)-1-pipera-                                 zinyl)-2-hydroxy-propyl]-N-methylsulphonyl-                                                               148-151                                             aniline                    (isopro-                                                                       panol)                                              2-Allyloxy-N-[2-hydroxy-3-(4-(2-pyridyl)-1-                                    piperazinyl)-propyl]-N-methylsulphonyl-aniline.                                                           175-181                                             Neutral oxalate            (methanol)                                          2-Allyloxy-N-[3-(4-(3-chloro-phenyl)-1-pipera-                                 zinyl)-2-hydroxy-propyl]-N-methylsulphonyl-                                                               150-155                                             aniline. Acid oxalate      (acetone)                                           2-Allyloxy-N-[3-(4-(4-chloro-phenyl)-1-pipera-                                 zinyl)-2-hydroxy-propyl]-N-methylsulphonyl-                                                               163-166                                             aniline. Acid oxalate      (acetone)                                           2-Allyloxy-N-[2-hydroxy-3-(4-(4-methoxy-phenyl)-                               1-piperazinyl)-propyl]-N-methylsulphonyl-aniline.                                                         116-118                                             Acid oxalate               (acetone)                                           2-Allyloxy-N-[3-(4-benzyl-1-piperazinyl)-2-                                    hydroxy-propyl]-N-methylsulphonyl-aniline.                                                                175-177.5                                           Difumarate                 (isopro-                                                                       panol)                                              2-Allyloxy-N-[2-hydroxy-3-(4-(2-methoxy-phenyl)-                               1-piperazinyl)-propyl]-N-methylsulphonyl-                                                                 170-173                                             aniline. Hydrochloride     (isopro-                                                                       panol)                                              2-Allyloxy-N-[3-(4-(2-fluoro-phenyl)-1-pipera-                                 zinyl)-2-hydroxy-propyl]-N-methylsulphonyl-                                                               159-165                                             aniline                    (isopro-                                                                       panol)                                              2-Allyloxy-N-(2-hydroxy-3-isopropylamino-                                      propyl)-N-(4-methyl-benzenesulphonyl)-aniline                                                             165-166                                             Hydrochloride              (isopro-                                                                       panol)                                              2-Allyloxy-N-(3-tert-butylamino-2-hydroxy-                                     propyl)-N-(4-methyl-benzenesulphonyl)-                                                                    126                                                 aniline. Hydrochloride     (ethyl                                                                         acetate)                                            2-Allyloxy-N-(2-hydroxy-3-pyrrolidino-propyl)-                                 N-(4-methyl-benzenesulphonyl)-aniline.                                                                    144-146.5                                           Hydrochloride              (isopro-                                                                       panol)                                              2-Allyloxy-N-(2-hydroxy-3-morpholino-propyl)-                                  N-(4-methyl-benzenesulphonyl)-aniline.                                                                    81-84                                               Hydrochloride              (isopro-                                                                       panol)                                              2-Allyloxy-N-[2-hydroxy-3-(2-phenoxy-ethylamino)-                              propyl]-N-(4-methyl-benzenesulphonyl)-aniline.                                                            143-145                                             Hydrochloride              (isopro-                                                                       panol)                                              2-Allyloxy-N-[2-hydroxy-3-(3-phenyl-propylamino)-                              propyl]-N-(4-methyl-benzenesulphonyl)-aniline.                                                            167-168                                             Neutral oxalate            (ethanol)                                           2-Allyloxy-N-[2-hydroxy-3-(4-methyl-1-piperazinyl)-                            propyl]-N-(4-methyl-benzenesulphonyl)-aniline.                                                            176-185                                             Dihydrochloride            (isopro-                                                                       panol)                                              2-Allyloxy-N-[3-(4-(4-ethyl-1-piperazinyl)-2-hydroxy-                          propyl)-N-(4-methyl-benzenesulphonyl)-aniline.                                                            159-164                                             Dihydrochloride            (isopro-                                                                       panol)                                              2-Allyloxy-N-[2-hydroxy-3-(4-propyl-1-pipera-                                  zinyl)-propyl]-N-(4-methyl-benzenesulphonyl)-                                                             144-148                                             aniline                    (isopro-                                                                       panol)                                              2-Allyloxy-N-[2-hydroxy-3-(4-(2-hydroxy-ethyl)-                                1-piperazinyl)-propyl]-N-(4-methyl-benzenesul-                                                            157-159                                             phonyl)-aniline. Dihydrochloride                                                                          (isopro-                                                                       panol)                                              2-Allyloxy-N-[3-(4-(4-chloro-phenyl)-1-pipera-                                 zinyl)-2-hydroxy-propyl]-N-(4-methyl-benzene-                                                             176-177                                             sulphonyl)-aniline. Neutral oxalate                                                                       (methanol)                                          2-Allyloxy-N-[2-hydroxy-3-(4-(2-pyridyl)-1-                                    piperazinyl)-propyl]-N-(4-methyl-benzenesulphonyl)-                                                       203-204.5                                           aniline. Neutral oxalate   (methanol)                                          2-Allyloxy-N-[2-hydroxy-3-(4-phenyl-1-piperazinyl)-                            propyl]-N-(4-methyl-benzenesulphonyl)-aniline.                                                            193-203                                             Hydrochloride              (methanol)                                          2-Allyloxy-N-[3-(4-(3-chloro-phenyl)-1-pipera-                                 zinyl)-2-hydroxy-propyl]-N-(4-methyl-benzene-                                                             177-179                                             sulphonyl)-aniline. Neutral oxalate                                                                       (acetone)                                           2-Allyloxy-N-[3-(4-benzyl-1-piperazinyl)-2-                                    hydroxy-propyl]-N-(4-methyl-benzenesulphonyl)-                                                            142-146                                             aniline. Dihydrochloride   (acetone)                                           2-Allyloxy-N-[3-(4-(4-fluoro-phenyl)-1-pipera-                                 zinyl)-2-hydroxy-propyl]-N-(4-methyl-benzene-                                                             191-194                                             sulphonyl)-aniline. Hydrochloride                                                                         (isopro-                                                                       panol)                                              2-Allyloxy-N-[2-hydroxy-3-(4-(4-methoxy-phenyl)-                               1-piperazinyl)-propyl]-N-(4-methyl-benzenesulphonyl)-                                                     211-214                                             aniline. Hydrochloride     (methanol)                                          2-Allyloxy-N-[2-hydroxy-3-(4-(2-methoxy-phenyl)-1-                             piperazinyl)-propyl]-N-(4-methyl-benzenesulphonyl)-                                                       161-165                                             aniline. Neutral oxalate   (isopro-                                                                       panol)                                              2-Allyloxy-N-[3-(4-(2-fluoro-phenyl)-1-piperazinyl)-                           2-hydroxy-propyl]-N-(4-methyl-benzenesulphonyl)-                                                          160-165                                             aniline. Hydrochloride     (isopro-                                                                       panol)                                              2-Allyloxy-N-(2-hydroxy-3-isopropylamino-                                      propyl)-N-(4-methoxy-benzenesulphonyl)-aniline.                                                           137-140                                             Hydrochloride              (isopro-                                                                       panol)                                              2-Allyloxy-N-(3-tert-butylamino-2-hydroxy-propyl)-                             N-(4-methoxy-benzenesulphonyl)-aniline.                                                                   129-130                                             Hydrochloride              (isopro-                                                                       panol)                                              2-Allyloxy-N-[2-hydroxy-3-(2-phenoxy-ethylamino)-                              propyl]-N-(4-methoxy-benzenesulphonyl)-aniline.                                                           162-164                                             Hydrochloride              (ethyl                                                                         acetate)                                            2-Allyloxy-N-[2-hydroxy-3-(3-phenyl-propylamino)-                              propyl]-N-(4-methoxy-benzenesulphonyl)-aniline.                                                           157-158                                             Neutral oxalate            (ethyl                                                                         acetate)                                            2-Allyloxy-N-(2-hydroxy-3-pyrrolidino-propyl)-                                 N-(4-methoxy-benzenesulphonyl)-aniline.                                                                   161-162.5                                           Hydrochloride              (ethyl                                                                         acetate)                                            2-Allyloxy-N-(2-hydroxy-3-morpholino-propyl)-N-                                (4-methoxy-benzenesulphonyl)-aniline.                                                                     124-127                                             Hydrochloride              (isopro-                                                                       panol)                                              2-Allyloxy-N-[2-hydroxy-3-(4-methyl-1-pipera-                                  zinyl)-propyl]-N-(4-methoxy-benzenesulphonyl)-                                                            191-193                                             aniline. Dihydrochloride   (isopro-                                                                       panol)                                              2-Allyloxy-N-[3-(4-ethyl-1-piperazinyl)-2-                                     hydroxy-propyl]-N-(4-methoxy-benzenesulphonyl)-                                                           147-150                                             aniline. Dihydrochloride   (isopro-                                                                       panol)                                              2-Allyloxy-N-[2-hydroxy-3-(4-n-propyl-1-pipera-                                zinyl)-propyl]-N-(4-methoxy-benzenesulphonyl)-                                                            181-184                                             aniline. Dihydrochloride   (acetone)                                           2-Allyloxy-N-[2-hydroxy-3-(4-(2-hydroxy-ethyl)-                                1-piperazinyl)-propyl]-N-(4-methoxy-benzene-                                                              195-197                                             sulphonyl)-aniline. Dihydrochloride                                                                       (methanol)                                          2-Allyloxy-N-[2-hydroxy-3-(4-phenyl-1-piperazinyl)-                            propyl]-N-(4-methoxy-benzenesulphonyl)-aniline.                                                           220-222                                             Hydrochloride              (isopro-                                                                       panol)                                              2-Allyloxy-N-[3-(4-benzyloxy-1-piperazinyl)-                                   2-hydroxy-propyl]-N-(4-methoxy-benzenesulphonyl)-                                                         144-147                                             aniline. Dihydrochloride   (acetone)                                           2-Allyloxy-N-[3-(4-(3-chloro-phenyl)-1-piperazinyl)-                           2-hydroxy-propyl]-N-(4-methoxy-benzenesulphonyl)-                                                         171-175                                             aniline. Neutral oxalate   (acetone)                                           2-Allyloxy-N-[2-hydroxy-3-(4-(4-methoxy-phenyl)-                               1-piperazinyl)-propyl]-N-(4-methoxy-benzenesulpho-                                                        161-164                                             nyl)-aniline. Neutral oxalate                                                                             (isopro-                                                                       panol)                                              2-Allyloxy-N-[2-hydroxy-3-(4-(2-pyridyl)-1-                                    piperazinyl)-propyl]-N-(4-methoxy-benzenesulphonyl)-                                                      183-185                                             aniline. Neutral oxalate   (acetone)                                           2-Allyloxy-N-[3-(4-(4-chloro-phenyl)-1-piperazinyl)-                           2-hydroxy-propyl]-N-(4-methoxy-benzenesulphonyl)-                                                         123-124                                             aniline. Acid oxalate      (acetone)                                           2-Allyloxy-N-[3-(4-(4-fluoro-phenyl)-1-piperazi-                               nyl)-2-hydroxy-propyl]-N-(4-methoxy-benzene-                                                              160-161.5                                           sulphonyl)-aniline. Neutral oxalate                                                                       (methanol)                                          2-Allyloxy-N-[2-hydroxy-3-(4-(2-methoxy-phenyl)-                               1-piperazinyl)-propyl]-N-(4-methoxy-benzene-                                                              185-188.5                                           sulphonyl)-aniline         (isopro-                                                                       panol)                                              2-Allyloxy-N-[2-hydroxy-3-(4-(2-fluoro-phenyl)-                                1-piperazinyl)-propyl]-N-(4-methoxy-benzene-                                                              175-179                                             sulphonyl)-aniline         (isopro-                                                                       panol)                                              2,6-Dichloro-N-benzenesulphonyl-N-[2-hydroxy-                                  3-(4-methyl-1-piperazinyl)-propyl]-aniline.                                                               239-243                                             Dihydrochloride            (acetone)                                           2,6-Dichloro-N-benzenesulphonyl-N-[2-hydroxy-3-                                                           131-134                                             (4-phenyl-1-piperazinyl)-propyl]-aniline                                                                  (isopro-                                                                       panol)                                              2,6-Dichloro-N-benzenesulphonyl-N-[2-                                          hydroxy-3-(4-(4-chloro-phenyl)-1-piperazinyl)-                                                            137-143                                             propyl]-aniline. Acid oxalate                                                                             (acetone)                                           2,6-Dichloro-N-benzenesulphonyl-N-[3-(4-benzyl-                                1-piperazinyl)-2-hydroxy-propyl]-aniline.                                                                 220-228                                             Dihydrochloride            (acetone)                                           2,6-Dichloro-N-benzenesulphonyl-N-[2-hydroxy-                                  3-(4-(4-methoxy-phenyl)-1-piperazinyl)-propyl]-                                                           131-136                                             aniline. Acid oxalate      (acetone)                                           2,6-Dichloro-N-benzenesulphonyl-N-[3-(4-(3-                                    chloro-phenyl)-1-piperazinyl)-2-hydroxy-propyl]-                                                          188-189                                             aniline. Acid oxalate      (methanol)                                          2,6-Dichloro-N-benzenesulphonyl-N-[2-hydroxy-                                  3-(4-fluoro-4-phenyl-1-piperazinyl)-propyl]-                                                              174-176                                             aniline. Acid oxalate      (isopro-                                                                       panol)                                              2,6-Dichloro-N-benzenesulphonyl-N-[2-hydroxy-                                  3-(4-(2-methoxy-phenyl)-1-piperazinyl)-propyl]-                                                           196-197                                             aniline. Acid oxalate      (isopro-                                                                       panol)                                              2,6-Dichloro-N-[2-hydroxy-3-(4-phenyl-1-pipera-                                zinyl-propyl]-N-(4-methyl-benzenesulphonyl)-                                                              230-234                                             aniline. Dihydrochloride   (acetone)                                           2,6-Dichloro-N-[2-hydroxy-3-(4-(4-methoxy-phenyl)-                             1-piperazinyl)-propyl]-N-(4-methyl-benzenesulphonyl)-                                                     164-169                                             aniline. Neutral oxalate   (acetone)                                           2,6-Dichloro-N-[2-hydroxy-3-(4-phenyl-1-piperazi-                              nyl)-propyl]-N-(4-methyl-benzenesulphonyl)-aniline.                                                       230-234                                             Acid oxalate               (acetone)                                           2,6-Dichloro-N-[3-(4-(4-benzyl-phenyl)-1-piperazi-                             nyl)-2-hydroxy-propyl]-N-(4-methyl-benzenesulphonyl)-                                                     185-187                                             aniline. Dihydrochloride   (acetone)                                           2,6-Dichloro-N-[3-(4-(4-chloro-phenyl)-1-                                      piperazinyl)-2-hydroxy-propyl]-N-(4-methyl-                                                               152-155                                             benzenesulphonyl)-aniline. Acid oxalate                                                                   (acetone)                                           2,6-Dichloro-N-[3-(4-(3-chloro-phenyl)-1-pipera-                               zinyl)-2-hydroxy-propyl]-N-(4-methyl-benzene-                                                             167-169                                             sulphonyl)-aniline. Acid oxalate                                                                          (acetone)                                           2,6-Dichloro-N-[3-(4-(4-fluoro-phenyl)-1-                                      piperazinyl)-2-hydroxy-propyl]-N-(4-methyl-                                                               167-169                                             benzenesulphonyl)-aniline. Acid oxalate                                                                   (acetone)                                           2,6-Dichloro-N-[2-hydroxy-3-(4-(2-methoxy-phenyl)-                             1-piperazinyl)-propyl]-N-(4-methyl-benzenesulphonyl)-                                                     192-195                                             aniline. Acid oxalate      (acetone)                                           3,4-Dichloro-N-[2-hydroxy-3-(4-methyl-1-pipera-                                zinyl)-propyl]-N-methylsulphonyl-aniline.                                                                 224                                                 Dihydrochloride            (ethanol)                                           3,4-Dichloro-N-[3-(4-(2-chloro-phenyl)-1-pipera-                               zinyl)-2-hydroxy-propyl]-N-methylsulphonyl-                                                               115-117                                             aniline. Hydrochloride     (ethanol)                                           3,4-Dichloro-N-[3-(4-(2-chloro-phenyl)-1-pipera-                               zinyl)-2-hydroxy-propyl]-N-methylsulphonyl-                                                               186                                                 aniline. Dihydrochloride   (ethanol)                                           3,4-Dichloro-N-[2-hydroxy-3-(4-(2-methoxy-phenyl)-                             1-piperazinyl)-propyl]-N-methylsulphonyl-aniline.                                                         209-210                                             Dihydrochloride            (isopro-                                                                       panol)                                              3,4-Dichloro-N-[2-hydroxy-3-(4-(4-methoxy-phenyl)-                             1-piperazinyl)-propyl]-N-methylsulphonyl-aniline.                                                         195                                                 Dihydrochloride            (ethanol)                                           3,4-Dichloro-N-[2-hydroxy-3-(4-phenyl-1-pipera-                                                           107-108                                             zinyl)-propyl]-N-methylsulphonyl-aniline.                                                                 (ethanol)                                           3,4-Dichloro-N-[2-hydroxy-3-(4-methyl-1-pipera-                                zinyl)-propyl]-N-(4-methyl-benzenesulphonyl)-                                                             250                                                 aniline. Dihydrochloride   (isopro-                                                                       panol)                                              3,4-Dichloro-N-[2-hydroxy-3(4-phenyl-1-pipera-                                 zinyl)-propyl]-N-(4-methyl-benzenesulphonyl)-                                                             163-164                                             aniline                    (isopro-                                                                       panol)                                              3,4-Dichloro-N-[ 2-hydroxy-3-(4-methyl-1-pipera-                               zinyl)-propyl]-N-(4-methoxy-benzenesulphonyl)-                                                            237-238                                             aniline. Dihydrochloride   (isopro-                                                                       panol)                                              3,4-Dichloro-N-[2-hydroxy-3-(4-methyl-1-pipera-                                zinyl)-propyl]-N-(4-methoxy-benzenesulphonyl)-                                                            152-153                                             aniline                    (ethanol)                                           3,4-Dichloro-N-[3-(4-(4-chloro-phenyl)-1-pipera-                               zinyl)-2-hydroxy-propyl]-N-(4-methoxy-benzene                                                             164-165                                             sulphonyl)-aniline. Dihydrochloride                                                                       (isopro-                                                                       panol)                                              3,4-Dichloro-N-[2-hydroxy-3-(4-(4-methoxy-phenyl)-                             1-piperazinyl)-propyl]-N-(4-methoxy-benzene-                                                              181-182                                             sulphonyl)-aniline. Dihydrochloride                                                                       (ethanol)                                           4-Acetylamino-N-[2-hydroxy-3-(4-methyl-1-piperazi-                             nyl)-propyl]-N-methylsulphonyl-aniline.                                                                   205-208                                             Dihydrochloride            (methanol)                                          4-Acetylamino-N-[3-(4-(4-chloro-phenyl)-1-pipera-                                                         167-168                                             zinyl)-2-hydroxy-propyl]-N-methylsulphonyl-aniline                                                        (ethanol)                                           4-Acetylamino-N-[2-hydroxy-3-(4-phenyl-1-piperazi-                                                        177-179                                             nyl)-propyl]-N-methylsulphonyl-aniline                                                                    (methanol)                                          4-Acetylamino-N-[2-hydroxy-3-(4-(4-methoxy-phenyl)-                                                       195-197                                             1-piperazinyl)-propyl]-N-methylsulphonyl-aniline                                                          (ethanol)                                           4-Acetylamino-N-[2-hydroxy-3-(4-(2-methoxy-phenyl)-                                                       130-133                                             1-piperazinyl)-propyl]-N-methylsulphonyl-aniline                                                          (ethanol)                                           4-Acetylamino-N-[3-(4-(2-chloro-phenyl)-1-piperazi-                                                       142-144                                             nyl)-2-hydroxy-propyl]-N-methylsulphonyl-aniline                                                          (isopro-                                                                       panol)                                              4-Acetylamino-N-[2-hydroxy-3-(4-phenyl-1-piperazi-                                                        175-177                                             nyl)-propyl]-N-(4-methyl-benzenesulphonyl)-aniline                                                        (ethanol)                                           4-Acetylamino-N-[2-hydroxy-3-(4-(4-methoxy-phenyl)-                            1-piperazinyl)-propyl]-N-(4-methyl-benzene-                                                               158-162                                             (sulphonyl)-aniline. Dihydrochloride                                                                      (methanol)                                          4-Acetylamino-N-[2-hydroxy-3-(4-(2-methoxy-                                    phenyl)-1-piperazinyl)-propyl]-N-(methyl-benzene-                                                         137-142                                             sulphonyl)-aniline. Hydrochloride                                                                         (ethanol)                                           4-Acetylamino-N-[3-(4-(2-chloro-phenyl)-1-pipera-                              zinyl)-2-hydroxy-propyl]-N-(4-methyl-benzene-                                                             170-172                                             sulphonyl] -aniline. Hydrochloride                                                                        (ethanol)                                           4-Acetylamino-N-[3-(4-(4-chloro-phenyl)-1-pipera-                              zinyl)-2-hydroxy-propyl]-N-(4-methyl-benzenesul-                                                          177-178                                             phonyl)-aniline            (ethanol)                                           N-[2-hydroxy-3-(4-methyl-1-piperazinyl)-propyl]-                                                          129-135                                             N-methylsulphonyl-4-amino-phenylacetamide                                                                 (isopro-                                                                       panol/                                                                         ether)                                              N-[2-hydroxy-3-(4-phenyl-1-piperazinyl)-propyl]-                                                          155-157                                             N-methylsulphonyl-4-amino-phenylacetamide                                                                 (ethanol)                                           N-[3-(4-(4-chloro-phenyl)-1-piperazinyl)-2-                                    hydroxy-propyl]-N-methylsulphonyl-4-amino-                                                                172-173                                             phenylacetamide            (ethanol)                                           N-[3-(4-(2-chloro-phenyl)-1-piperazinyl)-2-hydroxy-                            propyl]-N-methylsulphonyl-4-amino-phenyl-                                                                 177-178                                             acetamide                  (ethanol)                                           N-[2-hydroxy-3-(4-(4-methoxy-phenyl)-1-pipera-                                 zinyl)-propyl]-N-methylsulphonyl-4-amino-phenyl-                                                          171-172                                             acetamide                  (ethanol)                                           N-[2-hydroxy-3-(4-(2-methoxy-phenyl)-1-piperazi-                               nyl)-propyl]-N-methylsulphonyl-4-amino-phenyl-                                                            195-197                                             acetamide                  (ethanol)                                           N-[2-hydroxy-3-(4-methyl-1-piperazinyl)-propyl]-                               N(4-methyl-benzenesulphonyl-4-amino-phenyl-                                                               217-219                                             acetamide. Dihydrochloride (ethanol)                                           N-[2-hydroxy-3-(4-phenyl-1-piperazinyl)-propyl]-N-                                                        158-161                                             (4-methyl-benzenesulphonyl)-4-amino-phenylacetamide                                                       (ethanol)                                           N-[2-hydroxy-3-(4-(2-methoxy-phenyl)-1-pipera-                                 zinyl)-propyl]-N-(4-methyl-benzenesulphonyl)-4-                                                           145-147                                             amino-phenylacetamide      (ethanol)                                           N-[3-(4-(4-chloro-phenyl)-1-piperazinyl)-2-hydroxy-                            propyl]-N-(4-methyl-benzenesulphonyl)-4-amino-                                                            177-179                                             phenylacetamide            (ethanol)                                           N-[3-(4-(2-chloro-phenyl)-1-piperazinyl)-2-                                    hydroxy-propyl]-N-(4-methyl-benzenesulphonyl)-4-                                                          160-161                                             amino-phenylacetamide      (ethanol)                                           N-[2-hydroxy-3-(4-(4-methoxy-phenyl)-1-piperazinyl)-                           propyl]-N-(4-methyl-benzenesulphonyl)-4-amino-                                                            157-158                                             phenylacetamide            (ethanol)                                           ______________________________________                                    

Pharmaceutical compositions were prepared in accordance with known pharmaceutical techniques:

    ______________________________________                                         Ingredients                 mg                                                 ______________________________________                                         (1) Hard gelatin capsule                                                       2-Allyloxy-N-(3-tert-butylamino-2-hydroxy-                                     propyl)-N-(4-methoxy-benzenesulphonyl)-                                        aniline.                                                                       Hydrochloride               100                                                Starches                    99.5                                               Colloidal silicia           0.5                                                                            200.0                                              (2) Injectable solution                                                        2-Allyloxy-N-[3-(4-benzyl-1-piperazinyl)-2-                                    hydroxy-propyl]-N-(4-methyl-benzenesulphonyl)-                                 aniline. Dihydrochloride    150                                                Polysorbate 80              150                                                Benzyl alcohol              75                                                 Water to 3 ml                                                                  (3) Suppository                                                                2-Allyloxy-N-[2-hydroxy-3-(4-(2-methoxy-phenyl)-                               1-piperazinyl)-propyl]-N-methylsulphonyl-aniline.                              Hydrochloride               100                                                Mixture of saturated acid mono- and diglycerides                                                           1400                                               (C.sub.12 -C.sub.18)        1500                                               (4) Tablet                                                                     4-Acetylamino-N-[2-hydroxy-3-(4-phenyl-1-                                      piperazinyl)-propyl]-N-methylsulphonyl-aniline                                                             200                                                Lactose                     64                                                 Polyvinylpyrrolidone        6                                                  Sodium carboxymethyl starch 24                                                 Magnesium stearate          4                                                  Talc                        2                                                                              300                                                ______________________________________                                     

We claim:
 1. Compounds of the formula: ##STR8## and the pharmaceutically acceptable acid addition salts thereof, wherein R₁ and R₂, which are the same or different, represent an allyloxy, acetamide or carboxamide group or a hydrogen or chlorine atom, R₃ represents a methyl, phenyl, methylphenyl or methoxyphenyl group, R₄ represents a hydrogen atom and R₅ an isopropyl, terbutyl, 2-phenoxy-ethyl, 3-phenyl-propyl group, or R₄ and R₅ taken together form with the nitrogen atom a heterocycle such as pyrrole, morpholine or a substituted piperazine of the formula: ##STR9## wherein R₆ represents a straight-chain alkyl group containing from 1 to 3 carbon atoms, a 2-hydroxyethyl, a benzyl or a 2-pyridyl group or a phenyl group optionally substituted by either a halogen atom or by a methoxy radical.
 2. 2-Allyloxy-N-(3-tert-butylamino-2-hydroxy-propyl)-N-(4-methoxybenzenesulphonyl)-aniline.
 3. 2-Allyloxy-N-[2-hydroxy-3-(4-(2-methoxy-phenyl)-1-piperazinyl)-propyl]-N-methylsulphonyl-aniline.
 4. 2-Allyloxy-N-[3-(4-benzyl-1-piperazinyl)-2-hydroxy-propyl]-N-(4-methyl-benzenesulphonyl)-aniline.
 5. 4-Acetylamino-N-[2-hydroxy-3-(4-phenyl-1-piperazinyl)-propyl]-N-methylsulphonyl-aniline.
 6. The compound of claim 1 wherein R₁ is hydrogen, R₂ is allyloxy, R₃ is methyl, R₄ and R₅ taken together form with the nitrogen atom a piperazine radical wherein R₆ is 4-fluorophenyl.
 7. The compound of claim 1 wherein R₁ is hydrogen, R₂ is allyloxy, R₃ is 4-methoxyphenyl, R₄ and R₅ taken together form with the nitrogen atom a piperazine radical wherein R₆ is 2-pyridyl.
 8. The compound of claim 1 wherein R₁ is hydrogen, R₂ is allyloxy, R₃ is 4-methoxyphenyl, R₄ and R₅ taken together form with the nitrogen atom a piperazine radical wherein R₆ is 2-fluorophenyl.
 9. The compound of claim 1 wherein R₁ and R₂ are chlorine, R₃ is methyl, R₄ and R₅ taken together form with the nitrogen atom a piperazine radical wherein R₆ is 2-chlorophenyl.
 10. The compound of claim 1 wherein R₁ is hydrogen, R₂ is allyloxy, R₃ is 4-methoxyphenyl, R₄ and R₅ taken together form with the nitrogen atom a piperazine radical wherein R₆ is 2-methoxyphenyl.
 11. The compound of claim 1 wherein R₁ and R₂ are chlorine, R₃ is 4-methoxyphenyl, R₄ and R₅ taken together form with the nitrogen atom a piperazine radical wherein R₆ is 4-chlorophenyl.
 12. The compound of claim 1 wherein R₁ is hydrogen, R₂ is 4-acetylamino, R₃ is methyl, R₄ and R₅ taken together form with the nitrogen atom a piperazine radical wherein R₆ is 4-chlorophenyl.
 13. The compound of claim 1 wherein R₁ is hydrogen, R₂ is 4-acetylamino, R₃ is 4-methylphenyl, R₄ and R₅ taken together form with the nitrogen atom a piperazine radical wherein R₆ is phenyl.
 14. The compound of claim 1 wherein R₁ is hydrogen, R₂ is 4-acetylamino, R₃ is 4-methylphenyl, R₄ and R₅ taken together form with the nitrogen atom a piperazine radical wherein R₆ is 2-methoxyphenyl.
 15. The compound of claim 1 wherein R₁ is hydrogen, R₂ is 4-acetylamino, R₃ is 4-methylphenyl, R₄ and R₅ taken together form with the nitrogen atom a piperazine radical wherein R₆ is 2-chlorophenyl.
 16. The compound of claim 1 wherein R₁ and R₂ are hydrogen, R₃ is methyl, R₄ and R₅ taken together form with the nitrogen atom a piperazine radical wherein R₆ is 4-chlorophenyl.
 17. The compound of claim 1 wherein R₁ is hydrogen, R₂ is NH₂ COCH₂ --, R₃ is methyl, R₄ and R₅ taken together with the nitrogen atom form a piperazine radical wherein R₆ is 2-methoxyphenyl.
 18. The compound of claim 1 wherein R₁ is hydrogen, R₂ is NH₂ COCH₂ --, R₃ is 4-methylphenyl, R₄ and R₅ taken together with the nitrogen atom form a piperazine radical wherein R₆ is 2-methoxyphenyl.
 19. Method of treatment of angina pectoris whereby from 100 to 200 mg per day of at least one compound of formula I of claim 1 or a pharmaceutically acceptable acid addition salt thereof are administered to the said patient.
 20. Pharmaceutical composition for the treatment of angina pectoris containing as active ingredient at least one compound of formula I of claim 1, or a pharmaceutically acceptable acid addition salt thereof, together with an appropriate excipient or carrier therefor, the active ingredient being present in the amount of 100 milligrams to 200 milligrams per dosage unit form.
 21. Pharmaceutical composition according to claim 20 for oral or rectal administration.
 22. Pharmaceutical composition according to claim 20 in the form of an injectable solution. 